Vitamin D and its metabolites circulate in blood primarily bound to vitamin D–binding protein (DBP). DBP is a serum glycoprotein that is synthesized by the liver. DBP binds more than 85% of 1,25-hydroxyvitamin D and 24,25-dihydroxyvitamin D. Because of binding to other proteins, only 0.4% of 1,25-dihydroxyvitamin D circulates as free hormone. DBP transports the highly lipophilic vitamin D in blood and provides a reservoir of vitamin D that protects against vitamin D deficiency.
1,25-Dihydroxyvitamin D Receptor 1,25-Dihydroxyvitamin D exerts its actions primarily through binding to the nuclear vitamin D receptor (VDR), which is a member of the nuclear hormone receptor family. The VDR is a ligand-dependent transcription factor that binds to cognate DNA sequences (vitamin D response elements) as a heterodimer with the retinoid X receptor (RXR). Thus the primary action of 1,25-dihydroxyvitamin D is to regulate gene expression in its target tissues, including the small intestine, bone, kidneys, and parathyroid gland.
The genomic actions of 1,25-dihydroxyvitamin D mediated by the VDR occur over a period of hours to days. 1,25-Dihydroxyvitamin D also has rapid effects (seconds to minutes). For example, 1,25-dihydroxyvitamin D rapidly induces absorption of Ca++ by the duodenum. The VDR is also expressed in the plasma membrane of cells and is linked to rapid signaling pathways (e.g., G proteins, phosphatidylinositol-3′-kinase). Current molecular modeling has led to development of ligands that specifically bind
Hormonal Regulation of Calcium and Phosphate Metabolism to the nuclearversus the membrane-localized VDR, paving the way for selective treatment of disorders related to the rapid versus slow actions of 1,25-dihydroxyvitamin D with synthetic vitamin D analogues.
Regulation of [Ca++] and [Pi] by Small Intestine and Bone
An overview of the regulation of [Ca++] and Pi] by the action of PTH and 1,25-dihydroxyvitamin D on the small intestine, bone, and parathyroid glands is summarized in
Table 40.2 and in the following paragraphs. For details on renal handling of Ca++ , consult
Chapter 36.
Calcitonin isapeptidehormoneproducedbythemedullarycells,orC-cells,ofthethyroidgland.Calcitoninsecretionispositivelyregulatedbyserum[Ca++]viatheCaSR.Thecalcitoninreceptorisexpressedinosteoclasts,wherecalcitoninactsrapidlyanddirectlytoinhibitboneresorption.However,inhumans,calcitonindoesnotappeartoplayamajorroleinregulatingserumCa.Insupportofthisview,productionofexcesscalcitoninorcompleteabsenceofcalcitonin(e.g.,followingthyroidectomy)doesnotperturbserumCalevels.Morepotentformsofthehormone(e.g.,salmoncalcitonin)havebeenusedtherapeuticallyasanantiresorptiveinthetreatmentofPaget’s disease (characterizedbyexcessiveosteoclasticboneresorption)andinosteoporosis.Calcitoninisalsoausefulhistochemicalmarkerofmedullarythyroidcancer.